Human (and other vertebrate) immune responses comprise complex and intricately regulated sequences of events, involving cells of several different types. An immune response can be triggered when an antigen in a human body encounters an antigen-presenting cell (APC). The APC can capture the antigen and display a portion of it on its surface in a form that can be recognized by a helper T (Th) lymphocyte. Upon binding of a Th lymphocyte with the APC-displayed antigen, the Th lymphocyte can become activated. An activated Th lymphocyte promotes activation of lymphocytes of other types, the particular type(s) depending on the identity of the Th lymphocyte and the context in which the antigen is displayed by the APC. Various types of Th lymphocytes can, for example, promote activation of cytotoxic T cells or proliferation or differentiation of antigen-specific B cells. Th lymphocytes can activate other lymphocytes by secreting one or more polypeptide hormones designated cytokines. Th lymphocytes exhibit the CD4 antigen on their surface.
Functionally distinct types of Th cells have been described in humans. At least two types of Th cells have been characterized, based on the cytokines they produce. Type 1 Th cells (i.e., Th1 cells) can produce interleukin-2 (IL-2), interferon-gamma (IFN-g), and tumor necrosis factor-beta (TNF-b). Type 2 Th cells (i.e., Th2 cells) can produce IL-4, IL-5, IL-6, and IL-10.
Immune responses activated by Th1 cell activation (i.e., a ‘type 1 immune response’ or ‘Th1-mediated response’) are characterized by significant production of IFN-gamma and promotion of cytotoxic lymphocyte activity. Type 1 immune responses can be induced, for example, by the presence of bacteria in the human body. The cytotoxic lymphocytes activated in a Th1-mediated response are capable of recognizing and killing cells that display the Th1-activating antigen on their surface. Thus, induction of a type 1 immune response can lead to elimination from the body of antigen-bearing cells. Excessive or otherwise inappropriate induction of a type 1 immune response can cause damage to normal (i.e., non-diseased tissues) in a human.
Immune responses activated by Th2 cell activation (i.e., a ‘type 2 immune response’ or ‘Th2-mediated response’) are characterized by significant production of IL-4 and promotion of humoral immunity (e.g., production of immunoglobulins, particularly including IgE). Type 2 immune responses are commonly induced in response to chronic infections (e.g., parasitic infections), and tend to inhibit, prevent, or reverse type 1 immune responses. Type 2 immune responses will normally eliminate a pathogen from the body, and can thereby inhibit further infection by an infectious agent. However, type 2 immune responses generally do not eliminate all pathogen-infected or diseased cells from the body. Thus, cells which exhibit the antigen that induced the type 2 immune response may persist chronically in the body. This occurs particularly when antigen-bearing cells (e.g., virus-infected cells or tumor cells) induce inappropriate activation of a type 2 immune response, which can facilitate persistence of the antigen-bearing cells in a human body.
Inflammation is a normal localized immune response to invasion or injury caused by an infectious agent (e.g., a bacterium) or by a tumor. In a process analogous to the manner in which blood flow can increase the supply of glucose and oxygen to active muscle tissue during a period of exercise, an inflammatory response can increase the supply of elements of the immune system at a local disease (e.g., infection or tumor) site in order to mount an effective defensive immune response. An effective inflammatory response can be characterized by at least six events:
i) release of antigens from diseased or pathological cells at the disease site and secretion of chemotactic factors at the injured site;
ii) infiltration of the disease site by cells of the immune system;
iii) polarized type I or type II activation of the immune cells by the antigens released at the site;
iv) amplification of the inflammatory response over time, at least for a limited period;
v) elimination of the diseased or pathological cells by immune cells; and
vi) conversion of activated immune cells into memory cells which are capable of providing long-term protection against the antigen or antigen-bearing cells.
Cancer is one of the foremost causes of mortality and morbidity among humans. Many cancers are manifested by the existence of tumors, which are clumps or masses of cancer cells. In the past, cancer cells were generally believed to be non-immunogenic, since they are derived from autologous (i.e., ‘self’) tissue, which normally does not induce an immune response. However, tumor-reactive lymphocytes can be isolated from patients afflicted with many types of cancer (Lee et al., 1997, Blood 90:1611-1617).
A significant portion of tumor mass is made up of lymphocytes. These cells, designated tumor-infiltrating lymphocytes (TILs), typically produce cytokines (e.g., IL-4) that are characteristic of a type 2 inflammatory response (Roussel et al., 1996, Clin. Exp. Immunol. 105:344-352). It has been postulated that predominance of type 2 TILs support a type 2 inflammation in tumors that inhibits tumoricidal cytotoxic immune responses. It has furthermore been suggested that modulation of the type of immune response exhibited by TILs can have anti-cancer therapeutic effects (Gorelik et al., 1994, Cancer Immunol. Immunother. 39:117-126; Pellegrini et al., 1996, Cancer Immunol. Immunother. 42:1-8; Goedegebuure et al., 1997, Cell Immunol. 175:150-156; Fujimoto et al., 1997, J. Immunol. 158:5619-5626; Okamoto et al., 1997, Int. J. Cancer 70:598-605; Stein et al., 1998, Eur. J. Med. Res. 3:194-202; Li et al., 1998, J. Surg. Oncol. 67:221-227). However, despite this recent understanding regarding both types of inflammatory response, no course of treatment has previously been identified whereby a type 2 inflammatory response (i.e., one conducive to tumor survival or growth) can be converted to or overcome by a type 1 inflammatory response (i.e., one in which tumor growth slows or halts and tumor regression is enhanced).
Current cancer therapies (e.g., surgery, radiotherapy, and chemotherapy) are relatively inefficient, and have very debilitating side effects that lead to relapses and death. In view of the overwhelming toll of human mortality and morbidity associated with cancer, an urgent need remains for therapeutic compositions, kits, and methods which can slow or reverse tumor progression in humans while reducing morbidity and offering protection against tumor relapse. The present invention satisfies this need, at least in part, by providing therapeutic compositions, kits, and methods which can be used to reliably treat a variety of human cancers, reduce treatment-related morbidity (relative to prior art therapeutic methods), and offer protection against tumor relapse.